This invention pertains to tetradentate enediyne ligands and associated metal complexes, and their use in the treatment of cancers and infectious diseases.
The potent antitumor activity of the enediyne natural product antibiotics such as calicheamicin, dynemicin, esperamicin, and neocarzinostatin has fostered interest in the development of simple enediynes with low thermal barriers to formation of the lethal 1,4-benzenoid diradical intermediate (see, e.g., Nicolaou, et al., Angew. Chem., Int. Ed. Engl. 1991, 30, 1387; Lee, et al., J. Am. Chem. Soc. 1987, 109, 3466; Konishi, et al., J. Am. Chem. Soc. 1990,112, 3715; Golik, et al., J. Am. Chem. Soc. 1987, 109, 3461; Edo, et al., Tet. Lett., 1985, 26, 331). Such benzenoid diradicals are thought to be capable of cleaving DNA by H-atom abstraction. Benzenoid 1,4-diradicals can be formed via Bergman cyclization of a suitable enediyne.
To this end, carbocyclic enediyne frameworks, and more recently, novel metalloenediyne structures, have been described (see, e.g., commonly assigned published PCT/US00/04915, the entire contents of which are hereby incorporated by reference; Nicolaou, et al., J. Am. Chem. Soc. 1992, 114, 7360; Warner, et al., Science 1995, 269, 814; Kxc3x6nig, et al., J. Org. Chem. 1996, 61, 5258; Basak, et al., J. Chem. Soc., Perkin Trans 1 2000, 1955; Coalter, et al., J. Am. Chem. Soc. 2000, 122, 3112; Benites, et al., J. Am. Chem. Soc. 2000, 122, 7208.). The relative disposition of the alkyne termini and the nature of the ring closing are thought to provide steric contributions to the thermal barrier in the Bergman cyclization (Magnus, et al., J. Am. Chem. Soc. 1990, 112, 4986; Snyder, J. P., J. Am. Chem. Soc. 1990, 112, 5367).
The role of chelated transition metals in the Bergman cyclization of certain enediynes has been studied in some laboratories. Notably, the chelation of transition metals has been observed to reduce the thermal barrier in the Bergman cyclization of enediynes. However, heating to about 60xc2x0 C. is still required for activation of such complexes, which is a relatively high temperature, and limits the usefulness of such compounds from a therapeutic standpoint. This problem can be avoided in some instances by using photoexcitation (e.g., photodynamic therapy (xe2x80x9cPDTxe2x80x9d)), but such procedures are often limited in terms of therapeutic application, as a light source is required. In addition, long wavelength absorbing species are preferred in biological applications, which raises additional obstacles in terms of developing a therapeutic agent. Accordingly, there is a need for new enediyne ligands and metal complexes thereof, particularly such ligands and complexes that exhibit a lower energy barrier for undergoing the Bergman cyclization, and methods of therapeutically using such ligands and complexes.
The invention provides such tetradentate enediyne ligands and metal complexes thereof, and methods of using them in the treatment of cancer and infectious diseases. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
In one aspect, the invention provides novel tetradentate enediyne ligands that are thermally stable, yet react under photothermal conditions or thermally at about room temperature or slightly higher when complexed with one or more metal ions.
In another aspect, the invention provides a method of prophylactically or therapeutically treating cancer in a mammal (e.g., a human) comprising administering a therapeutically effective amount of a compound of the invention. The compound can be administered alone or as a composition that includes a therapeutically acceptable carrier. In accordance with the invention, the free uncomplexed ligand can be administered to the mammal, such that the ligand contacts a metal in vivo and forms a metal complex in vivo. Alternatively, a metal complex of the invention can be administered to the mammal so as to prophylactically or therapeutically treat cancer and/or an infectious disease in accordance with the invention.
The method of the present invention also includes administering a metal-complexed ligand to a mammal such that the complex contacts and exchanges with a metal in vivo which, in turn, forms a new metal complex in vivo.